UC San Diego

CD8⁺ T cells posses the dual function of specifically targeting and killing host cells harboring intracellular pathogens, while at the same time maintaining the ability to "remember" the invader and protect against subsequent infection. The cellular decision to terminally differentiate as an effector cell or to maintain the ability to renew and persist as a memory call are guided in large part by the complex interaction of extracellular signaling leading to differential expression of various transcription factors. These factors co-operate to direct CD8⁺ T cells through their dramatic expansion and differentiation to effector and memory cells. Utilizing the unparalleled breadth of data and metadata from the Immunological Genome Project and conditional deletion of CD8⁺ associated transcription factors, we analyzed antigen -specific CD8⁺ T cells throughout differentiation to establish dynamic gene-expression signatures and identify putative transcriptional regulators throughout the response to infection. Notably, these gene-expression signatures can predict memory-precursor potential of effector CD8⁺ T cells. While distinct inflammatory milieu and T cell precursor frequencies are known to shift differentiation of CD8⁺ effector and memory populations, we found that core transcriptional signatures were nearly identically regulated, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Ultimately, long-lived memory CD8⁺ T cells stably expressed of a small subset of genes shared by NKT and a subset of [gamma][delta] T cells, consistent with common effector capacities. Meta-data analyses led to the discovery of Zeb2, a transcription repressor, which we subsequently showed is necessary for the formation of the subset of terminally differentiated effector CD8⁺ T cells. These results provide a framework for the future study of T cell differentiation during infection and provide insight into transcriptional regulation influencing immunological memory formation and vaccine efficacy